Besides of the intrinsic effectiveness of chemotherapy a second factor had to be taken into consideration. Compliance of patients with the scheduled chemotherapy was poor. A thoracotomy is a significant surgical procedure and requires some time to recover. Besides, by the time when those trials were conducted supportive measures (antiemetic therapy and colony-stimulating stimulating factors mainly) were suboptimal.

Modern trials with AC

After the results of the above mentioned meta-analysis were published, several trials comparing cisplatin-based schemes vs. observation were conducted. We will review them and a brief summary of their characteristics is also presented in Table 1.

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Table 1. Modern clinical trials of adjuvant chemotherapy in NSCLC

Trial N Stage Chemotherapy RT Survival (%) Chemo/Obs P Comments
ALPI (6) 1,088 I-IIIA MVP ± +1/- 0.59
IALT (7) 1,867 I-IIIA CDDP-based ± 44/40 0.03 not maintained >5 years
BLT (8) 381 I-IIIA CDDP-based ± 58/60 0.90 At 2 years
CALGB 9633 (9) 344 IB P + Cb 60/58 0.12
JBR 10 (10) 482 IB-II VNR + CDDP 69/54 0.003 Maintained at 9 years for stage II
ANITA (11) 840 I-IIIA VNR + CDDP ± 66/44 months (median) 0.02 Maintained at 7 years for stages II-IIIa
Note: ALPI, The Adjuvant Lung Project; IALT, International Adjuvant Lung Cancer Trial; ANITA, the Adjuvant Navelbine International Trialist Association; MVP, mitomycin, ifosfamide, cisplatin; RT, radiotherapy; Obs, observation; Cb, carboplatin; P, paclitaxel; VNR, vinorelbine; NSCLC, non-small cell lung cancer.

The Adjuvant Lung Project (ALPI) was the first reported (and the last negative) of these trials (6). It was a large trial with 1,209 patients enrolled. Stages I,II and IIIA were included and randomization arms were mitomycin, vindesine and cisplatin (MIC) for three cycles or no treatment. This trials found no differences between arms in survival [HR 0.96 (95% CI, 0.81-1.13, P=0.59)] or progression-free survival [HR 0.89 (95% CI, 0.76-1.03, P=0.13)]. Only 69% of the patients received the three planned courses and grade IV neutropenia occurred in 12% of patients.

A second negative trial was published (8). However, this trial was smaller (381 patients) and probably did not meet quality standards to be taken into account: 3% of the patients received pre-operative chemotherapy, 5% did not reached complete resections, multiple chemotherapy schemes were allowed and 13% did not even started scheduled therapy. No benefit in survival was found [HR 1.02 (95% CI, 0.77-1.35, P=0.90)] and 30% of the patients had grades III,IV toxicity.

The, up to now, larger evidence for AC in this setting comes from the International Adjuvant Lung Cancer Trial (IALT) (7). It included 1,867 patients with resected stages I to IIIA. Of them, 932 patients were allocated to the chemotherapy arm and 74% received a Cisplatin dose of 240 mg/m2 or more. Chemotherapy included three or four courses of Cisplatin based chemotherapy along with either etoposide (56.5% of the patients) vinorelbine (26.8%) vinblastine (11.0%) or vindesine (5.8%). AC arm had a significant higher survival rate than the observation arm [44.5% vs. 40.4% at 5 years; HR 0.86 (95% CI, 0.76-0.98, P<0.03)]. Progression-free survival was also superior [39.4 vs. 34.3 at 5 years [HR 0.83 (95% CI, 0.74-0.94, P<0.003)]. There were a 0.8% of chemotherapy-related deaths.

JBR.10 (10) was a trial conducted in Canada and USA. A total of 482 patients with resected NSCLC were included. Chemotherapy was vinorelbine 25 mg/m2 weekly for 16 weeks plus cisplatin 50 mg/m2 on days 1 and 8, for four courses. Forty-five percent of the patients were stage IB and 55% stage II (excluding T3N0 patients). Chemotherapy significantly prolonged progression-free survival as compared with observation [HR 0.60 (95% CI, 0.45-0.79, P<0.001)] and survival at 5 years [69% vs. 54% (HR 0.78)]. Subgroup analysis showed no survival benefit for stage IB patients (P=0.79) whilst for stage II median survival was 80 months for the chemotherapy arm vs. 41 months for the observation arm [HR 0.59 (95% CI, 0.42-0.85, P=0.004)]. In this trial the most common toxicity was hematologic (with 7% of febrile neutropenia) and there were two treatment-related deaths. A study of quality of life (QoL) was conducted in a subset of 359 patients. Chemotherapy was associated with a transient worsening in QoL due to nausea, vomiting and fatigue but returned to baseline by 9 months (except for neurotoxicity).

The trial conducted by the Adjuvant Navelbine International Trialist Association (ANITA) (11) also randomized patients with stage Ib, II or IIIa to a cisplatin-vinorelbine combination (Vinorelbine 30 mg/m2 weekly for 16 weeks plus cisplatin 100 mg/m2 day 1 every 4 weeks, 4 courses scheduled) or observation. Chemotherapy significantly improved median survival (65.7 vs. 43.7 months) with an 8.6% absolute benefit at 5 years [HR 0.80 (95% CI, 0.66-0.96, P=0.02)]. Neutropenia was the main toxicity (9% febrile neutropenia) with 2% toxic deaths.

One more trial has to be mentioned (9) although with some caveats in mind. CALGB 9633 was relatively small (344 patients) and was the only large trial which used carboplatin AUC 6 (instead of cisplatin) along with paclitaxel 200 mg/m2. Four courses given every 3 weeks were scheduled. It is also remarkable that only patients with resected stage IB disease were included. In a preliminary report with 34 months median follow-up AC was associated with a significant improvement in progression-free and overall survival. However, with a longer median follow-up of 74 months differences in survival were non-significant [HR 0.83 (95% CI, 0.64-1.08, P=0.12)]. All these factors (insufficient statistical power, early stop, carboplatin use, stage IB) may have influenced the results. Subsequently, an exploratory analysis showed benefit for patients whose tumors were 4 cm in diameter or larger (HR 0.69).